Retention of ERK in the cytoplasm mediates the pluripotency of embryonic stem cells

The dynamic subcellular localization of ERK1/2 plays an important role in regulating cell fate. Differentiation of mouse embryonic stem cells (mESCs) involves inductive stimulation of ERK1/2, and therefore, inhibitors of the ERK cascade are used to maintain pluripotency. Interestingly, we found that in pluripotent mESCs, ERK1/2 do not translocate to the nucleus either before or after stimulation. This inhibition of nuclear translocation may be dependent on a lack of stimulated ERK1/2 interaction with importin7 rather than a lack of ERK1/2 phosphorylation activating translocation. At late stages of naive-to-primed transition, the action of the translocating machinery is restored, leading to elevation in ERK1/2-importin7 interaction and their nuclear translocation. Importantly, forcing ERK2 into the naive cells’ nuclei accelerates their early differentiation, while prevention of the translocation restores stem cells’ pluripotency. These results indicate that prevention of nuclear ERK1/2 translocation serves as a safety mechanism for keeping pluripotency of mESCs.